Sensory neurons of the dorsal root ganglia (DRGs) and trigeminal nerve can detect environmental changes through projections in the skin. These neurons comprise three main classes devoted to nociception/puritoception, mechanosensation and proprioception. Nociception is the process by which noxious stimuli such as heat and touch cause the sensory neurons (nociceptors) in the skin to send signals to the central nervous system. Puritoception is the perception of itch. Mechanosensation is the detection of pressure, and proprioception is the detection of muscle movement through the monitoring of muscle stretch. The control of pain, itch and disorders that affect various types of sensory neurons has long been a major challenge for pharmacotherapy. It was reported that at least 116 million Americans and 35% of the population worldwide suffer from chronic neuropathy or pain (Elzahaf et al., Curr. Med. Res. Opin. 28, 1221-1229, 2012). However, only 30% of patients in chronic pain respond to “gold standard” FDA approved treatments (Finnerup et al., Pain 150, 573-581, 2010). Laboratory studies have demonstrated a large range of inter-individual variation in response to identical pain stimuli. Furthermore, it is becoming increasingly recognized that genetic factors are a major contributor to pain phenotype and response to pharmacological treatments. Despite these findings, much pain related drug discovery has relied on animal models, which are unlikely to be useful in modeling subtle differences between humans and have lower throughput than in vitro screens. These factors may help to explain the staggeringly high rates of attrition during clinical trials for even promising preclinical candidates. The control and detection of itch is poorly understood and also a significant unmet medical need. Although cadaveric human sensory neurons are available for research, these cells cannot be genetically altered and have limited availability.
There is a need in the art for effective means for generating functionally responsive sensory neurons in vitro in sufficient numbers for mechanistic studies or drug screening. The present invention is directed to this and other unmet needs in the art.